DESCRIPTION: (Verbatim from the Applicant's Abstract) Polyglutamine expansion causes Huntington's disease (HD) and seven other inherited neurodegenerative disorders. A central question about these diseases is how polyglutamine expansion induces the selective neuropathology in each disorder. In HD, selective neuronal loss occurs in the striatum and the deep layers of the cerebral cortex while the disease protein huntingtin is widely expressed. Recent studies have shown that polyglutamine expansion causes N-terminal huntingtin to aggregate, to accumulate in the nucleus, and to interact abnormally with other proteins. However, intranuclear huntingtin aggregates are not causally associated with neurodegeneration. Our recent fmdings indicate that mutant huntingtin also forms aggregates in neuropil and axonal terminals and suggest that the formation of neuropil aggregates is highly correlated with neurological symptoms in HD mice. Since huntingtin aggregates are composed of N-terminal fragments of mutant huntingtin, we hypothesize that N-terminal mutant huntingtin in the neuropil induces synaptic dysfunction that contributes to the early neuropathology of HD. To test this idea, we will (1) examine whether N-terminal huntingtin fragments preferentially form axonal aggregates in HD-affected striatal neurons, (2) study whether mutant N-terminal huntingtin abnormally binds to synaptic vesicles, and (3) investigate whether N-terminal mutant huntingtin affects neurotransmitter uptake or release of synaptic vesicles. These studies aim to provide insights into the mechanism of the specific neuropathology of HD and to help develop an effective strategy for the treatment of HD.